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Abstract

Introduction: Muscle wasting is frequently observed in patients with heart failure, and is an independent risk factor in these patients. Resistance exercise exerts beneficial effects for these patients, however the mechanisms are largely unknown. It has been proposed that skeletal muscle secretes factors that influence the behavior of remote cells. Recent evidence indicates that circulating miRNAs are involved in cardiovascular diseases.

Hypothesis: We assessed the hypothesis that cardio-protective miRNAs are secreted from growing skeletal muscle.

Methods: To identify muscle-derived miRNAs, we utilized skeletal muscle-specific, conditional transgenic mice, that can induce the growth of functional muscle by switching Akt1 signaling on in muscle fibers (Akt1 TG mice). Two weeks after Akt1 activation in skeletal muscle, we isolated miRNA from gastrocnemius muscle in Akt1 TG and control mice (n=4 in each group). We also isolated exosomal miRNA from serum in each mouse. The miRNA expression was comprehensively analyzed by miRNA PCR array. Adenovirus-mediated Akt1 overexpression experiments were performed in L6 myotubes. Secreted miRNA in culture media was evaluated by quantitative real-time PCR.

Results: Activation of Akt1 signaling in myofibers led to an increase in skeletal muscle mass, assessed by gastrocnemius muscle weight at 14 days after transgene induction (171.5 vs. 241.3 mg; p<0.001). Based on the PCR array screening, we found that 12 miRNAs were significantly upregulated in gastrocnemius muscle following Akt1 transgene induction. Among them, 4 miRNAs (miRNA-155, -215, -9, and -96) were increased in exosome isolated from serum in Akt1 TG mice. Furthermore, miRNA-96 was robustly upregulated in exosome isolated from culture media of L6 myotubes transfected with constitutive-active Akt1, suggesting that it was derived from muscle cells.